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PreprintCited by 9Acute Lymphoblastic Leukemia researchGenomics and Chromatin DynamicsEpigenetics and DNA Methylation

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PU.1 Eviction at Lymphocyte-Specific Chromatin Domains Mediates Glucocorticoid Response in Acute Lymphoblastic Leukemia

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Jing, Duohui, Beck, Dominik, Cao, Honghui, Tian, Feng, Huang, Yizhou, Zhao, Han, Tai, Xiaolu, XU, WENQIAN, Kosasih, Hansen, Kealy, David, Bridge, Katherine, Zhao, Weiye, Holding, Andrew, Dowle, Adam, Taylor, Samuel, Song, Gaoxian, Fajardo, Diego, Walia, Yashna, Wang, Meng, Zhang, Chao, Wang, Jin, Mi, Jian-Qing, Lock, Richard, de Bock, Charles·2024·Nature Communications
DOI 10.21203/rs.3.rs-3872306/v1PMC PMC11549222

Preprint — published as 10.1038/s41467-024-54096-2 · Paper page

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Abstract

The epigenetic landscape plays a critical role in the onset and evolution of various malignancies, but its therapeutic utility remains underutilized. Glucocorticoids are an essential part of many multi-agent treatment regimens for lymphoid malignancies. However, the emergence of glucocorticoid resistance is a significant barrier to cure, which is in part due to epigenetic alterations, including aberrant chromatin accessibility and hypermethylation at lymphocyte-specific glucocorticoid-response elements (GREs). To gain a deeper understanding of regulatory mechanisms leading to these epigenetic alterations, we conducted a multi-omics study, including chromosome conformation capture sequencing (HiC), to examine changes in the 3D genome structure following the in vivo treatment of acute lymphoblastic leukemia (ALL) patient-derived xenografts (PDXs) with glucocorticoid. We found that glucocorticoid treatment led to distinct patterns of topologically associated domains (TADs) in glucocorticoid sensitive compared to resistant PDXs. Furthermore, we show that these TADs were primed by the development-related pioneer transcription factor PU.1, which extensively interacts with the glucocorticoid receptor (GR) exclusively in glucocorticoid-sensitive ALL PDXs. An integrative analysis of rapid immunoprecipitation mass spectrometry of endogenous protein (RIME) and ChIP-seq revealed that PU.1 binding was associated with lymphocyte-specific activation of GREs and GRE-interacting super-enhancers. The PU.1-associated TADs modulated epigenetic marks, and particularlythe eviction of PU.1 promoted GR binding and the expression of signature genes, including BIM, ZBTB16 and RASA1, mediating glucocorticoid-induced apoptosis in ALL. These findings were phenocopied using a PU.1 inhibitor DB2313 to restore glucocorticoid sensitivity in ALL. Taken together, this study identified a new epigenetic pathway integrating PU.1 priming and PU.1-GR interaction which ultimately leads to PU.1 eviction in ALL. This pathway provides the first link between the activity of a lineage-specific transcription factor and epigenetic modulators mediating the response to glucocorticoids and thus offers a new avenue to translate fundamental epigenetic research into the clinic.

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Metadata

Authors
Jing, D., Beck, D., Cao, H., Tian, F., Huang, Y., Zhao, H., Tai, X., XU, W., Kosasih, H., Kealy, D., Bridge, K., Zhao, W., Holding, A., Dowle, A., Taylor, S., Song, G., Fajardo, D., Walia, Y., Wang, M., Zhang, C., Wang, J., Mi, J.-Q., Lock, R., & de Bock, C.
Affiliations
  • Shanghai Jiao Tong University (CN)
  • University of Technology Sydney (AU)
  • Hebei University of Engineering (CN)
  • UNSW Sydney (AU)
  • University of York (GB)
  • Albert Einstein College of Medicine (US)
Corresponding author
  • Jing, Duohui
  • Beck, Dominik
  • Lock, Richard
  • de Bock, Charles
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-02-15
Volume
15
Issue
1
Pages
9697-9697
ISSN
2041-1723 (ISSN-L)
DOI
10.21203/rs.3.rs-3872306/v1
PMC
PMC11549222
OpenAlex
W4404167560
Cited by
9
References
100
Citations by year
2026: 3 · 2025: 6
FWCI
3.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • OPUS - Open Publications of UTS Scholars (University of Technology Sydney) (submittedVersion, cc-by-nc-nd)
  • UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Neuroscience Research Australia
  • Yorkshire Forward (EP/K039660/1, EP/M028127/1)
  • Kay Kendall Leukaemia Fund (KKL1377)
  • Research Councils UK (EP/K039660/1, EP/M028127/1)
  • Deutsche Forschungsgemeinschaft (EP/M028127/1, EP/K039660/1)
  • University of New South Wales
  • University of Sydney
  • University of Technology Sydney
  • National Natural Science Foundation of China (82270155, 32271165, 82270187, 82070227, 82050410359, 82070144)
  • Science and Technology Commission of Shanghai Municipality (21430711800, 23141903000)
  • Shanghai Jiao Tong University
  • Hebei University
  • Chinesisch-Deutsche Zentrum für Wissenschaftsförderung
  • Hebei University of Engineering
  • Kids Cancer Alliance
  • Ruijin Hospital
  • Translational Cancer Research Network
  • Centre for Blood Research, University of British Columbia
  • Medical Research Council
  • Engineering and Physical Sciences Research Council (EP/M028127/1, EP/K039660/1)
  • Biotechnology and Biological Sciences Research Council (BB/Y51424X/1, BB/X018288/1, EP/M028127/1, BB/W019272/1, EP/K039660/1, BB/V000071/1)
  • National Health and Medical Research Council (1181666, 1157871)
  • School of Medicine, Shanghai Jiao Tong University
  • Faculty of Medicine and Health, University of Sydney
Topics
  • Health Sciences › Medicine › Hematology › Acute Lymphoblastic Leukemia research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
PU.1, glucocorticoid resistance, acute lymphoblastic leukemia, glucocorticoid receptor, chromatin organization, pioneer transcription factors, epigenetic regulation, apoptosis, drug response
MeSH terms
Proto-Oncogene Protein Spi-1, Animals, Chromatin, Female, Glucocorticoids, Humans, Lymphocytes, Proto-Oncogene Proteins, Receptors, Glucocorticoid, Trans-Activators, Gene Expression Regulation, Leukemic, Apoptosis, Drug Resistance, Neoplasm, Response Elements, Xenograft Model Antitumor Assays, Epigenesis, Genetic, Cell Line, Tumor, Mice, Precursor Cell Lymphoblastic Leukemia-Lymphoma

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